A genetic mutation may disrupt the movement of materials in and out of a cell’s nucleus, destroying neurons and leading to the development of forms of amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD).

The research, published in Nature and Nature Neuroscience, was conducted by three teams of researchers from St. Jude’s Children’s Research Hospital, Johns Hopkins University, and Stanford University. The scientists found that a mutation in the C9orf72 gene prevents the movement of proteins and RNA between the cell nucleus and cytoplasm, disrupting the flow of genetic information. This culminates in a problem with gene expression and eventually neuron death, resulting in the paralysis and cognitive degeneration associated with ALS and FTD.

The mutated C9orf72 gene, which is responsible for 40% of inherited ALS cases, 25% of inherited FTD cases, and 10% of spontaneous cases of each disorder, is made up of repetitive stretches of six nucleotides that produce RNA that can interfere with protein activity. The RNA also generates toxic depeptide repeat proteins. Evidence collected from neurons grown from patients’ skin cells indicate that affected neurons have an increased amount of RNA in the nucleus compared to healthy control cells, while the neurons also appear to struggle to transfer proteins into the nucleus.

“This research defines the tipping point for how both ALS and FTD start, which is the interruption of nuclear-cytoplasmic transport,” said Jeffrey Rothstein, MD, PhD, of Johns Hopkins University. “By examining a combination of fly models, living human brain cells, and real human tissue from autopsies, these studies comprehensively teach us what starts the disease.”

Rothstein and colleagues focused on a specific protein, RanGap, which plays a role in nucleocytoplasmic transport, and found that the defective RNA binds to the protein in brain tissue of patients with the genetic mutation, which stops the protein from being able to function. Compounds intended to prevent the interference eliminated the transport defect, allowing RanGap to enter the nucleus. Additionally, the researchers found that increasing production of RanGap in fruit flies reduced neuronal degeneration and motor problems associated with the mutation, indicating a possible pharmacotherapeutic intervention.

Researchers led by J. Paul Taylor, MD, PhD, of St. Jude’s, tested the mutation’s effect on neurons by multiplying the repetitive DNA sequence in fruit fly neurons eight, 28, and 58 times. They found that the more copies of the sequence there were, the more harm was done to the cell. The team then identified 18 genes related to nucleocytoplasmic transport which could potentially increase of decrease damage to the cell. Research conducted by Aaron Gitler, PhD, of Stanford University, and colleagues confirmed the findings by Taylor’s group: that specific genes involved in nuclear transport have influence over how harmful the toxic dipeptide repeat proteins are to cells.

Together, the findings suggest that pharmacotherapies designed to increase nucleocytoplasmic transport may be an effective treatment for some forms of ALS and FTD.